The AIDS epidemic is one of the most challenging problems in medicine in the 21st century. A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a vitally encoded protease to generate mature vital proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. It has been previously demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Among many strategies to combat this disease, highly active antiretroviral therapy (HAART) with HIV protease inhibitors (PIs) in combination with reverse transcriptase inhibitors (RTIs) continues to be the first line treatment for control of HIV infection. This treatment regimen has definitely improved quality of life, enhanced HIV management, and halted the progression of the disease. However, despite these impressive successes, there remain many challenges to treating this devastating disease, including decreasing both the toxicity of and complexity of these treatment regimens. In addition, there is a growing population of patients that are developing multi-drug resistant strains of HIV, and there is ample evidence that these strains can be further transmitted.
HAART has had a major impact on the AIDS epidemic in industrially advanced nations; however, eradication of human immunodeficiency virus type 1 (HIV 1) appears to be currently unachieved, in part due to the viral reservoirs remaining in blood and infected tissues. The limitation of antiviral therapy of AIDS is also exacerbated by complicated regimens, the development of drug-resistant HIV-1 variants, and a number of inherent adverse effects. However, a number of challenges have nonetheless been encountered in bringing about the optimal benefits of the currently available therapeutics of AIDS and HIV-1 infection to individuals receiving HAART. They include (i) drug-related toxicities; (ii) partial restoration of immunologic functions once individuals developed AIDS; (iii) development of various cancers as a consequence of survival prolongation; (iv) flame-up of inflammation in individuals receiving HAART or immune re-construction syndrome (IRS); and (v) increased cost of antiviral therapy. Such limitations of HAART are exacerbated by the development of drug-resistant HIV-1 variants.
Without being bound by theory, it is believed that successful antiviral drugs exert their virus-specific effects by interacting with viral receptors, virally encoded enzymes, viral structural components, viral genes, or their transcripts without disturbing cellular metabolism or function. However, at present, it is believed that current antiretroviral drugs and agents are unlikely to be completely specific for HIV-1 or to be devoid of toxicity or side effects in the therapy of AIDS. Those issues are of special note because patients with AIDS and its related diseases will have to receive antiretroviral therapy for a long period of time, perhaps for the rest of their lives.
The invention described herein includes novel compounds and compositions for treating patients in need of relief from HIV, AIDS, and AIDS-related diseases. In addition, the invention described herein includes methods for treating HIV, AIDS, and AIDS-related diseases using the compounds described herein as well as known compounds that heretofore have not been used or described as being useful in the treatment of such diseases.
The compounds described herein may be used in the treatment of HIV, AIDS, and AIDS-related diseases. Without being bound by theory, it is suggested that the compounds described herein may exert their utility by the inhibition of proteases encoded by human immunodeficiency virus (HIV), such as HIV-1. The compounds or pharmaceutically acceptable salts thereof, are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS), either as compounds, pharmaceutically acceptable salts, or pharmaceutical composition ingredients. It is appreciated that the compounds described herein may be used alone or in combination with other compounds useful for treating such diseases, including those compounds that may operate by the same or different modes of action. Further, it is appreciated that the compounds and compositions described herein may be administered alone or with other compounds and compositions, such as other antivirals, immunomodulators, antibiotics, vaccines, and the like.
In one illustrative embodiment, a compound of the following Formula I is described.
or a pharmaceutically acceptable salt, isomer, mixture of isomers, crystalline form, non crystalline form, hydrate, or solvate thereof; wherein
R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
Q1 is a cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each of which is optionally substituted;
X1A is a bond, —N(R17)—, —S(O)q—, or optionally substituted alkylene; and R1A is —S(O)2R14, —C(O)R12, —N(R8)R9, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted, or R1A and X1A together with the attached nitrogen form an optionally substituted heterocyclyl;
X2 is —C(O)—, —S(O)n—, or optionally substituted alkylene;
X3 is —C(O)— or —S(O)p—;
X4 is a bond, —C(O)—, —S(O)q—, —N(R17)—, optionally substituted alkylene, —CH(C(O)R12)—, or —CH(S(O)nR11)—;
X5 is a bond, —N(R17)—, —S(O)q—, or optionally substituted alkylene;
R2 and R3 are each independently selected from the group consisting of hydrogen, —S(O)2R14, —C(O)R12, —N(R8)R9, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted; R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, —OH, —NO2, —N(R8)R9, —OR10, —S(O)nR11, —C(O)R12, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted; or R3, R4, X4 and the attached nitrogen form an optionally substituted heterocyclyl;
p is independently 1 or 2 in each instance; and n and q are each independently 0, 1, or 2 in each instance;
R20 is hydrogen, or a prodrug forming group;
R8 is in each instance independently selected from the group consisting of hydrogen, —C(O)R13, —S(O)2R14, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R9 is in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R10 is in each instance independently selected from the group consisting of —C(O)R13, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R11 is in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, when n is 0; R11 is in each instance independently selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, when n is 1; and R11 is in each instance independently selected from the group consisting of —N(R15)R16, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, aryl alkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, when n is 2;
R12 and R13 are each independently selected from the group consisting of hydrogen, —OR19, —N(R18)R19, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R14 is in each instance independently selected from the group consisting of hydrogen, —N(R18)R19, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted; and
R15, R16, R17, R18, and R19 are in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
with the proviso that the compound is not

In another illustrative embodiment, a compound of the following Formula II is described.
and solvates, hydrates and pharmaceutically acceptable salts thereof; wherein:
W and Z are independently selected from the group consisting of a bond and a divalent group CRA, CRA2, N, NRA, O, S(O)m and covalently bonded combinations thereof; where m is an integer from 0 to 2; providing that neither W nor Z comprises O—O, or O—S(O); and providing that W, Z, and the attached carbons form at least a five-membered ring;
bonds a, b, c, and d are each independently selected from the group consisting single bond, double bond, and aromatic bond;
RA is in each instance independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, halo, nitro, cyano, OR13A, SR13A, S(O)R13A, SO2R13A, NR13AR14A, CO2R13A, CONR13AR14A, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted; where R13A and R14A are each independently selected in each instance from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, or R13A and R14A together with the attached nitrogen form an optionally substituted heterocyclyl;
R1 is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted; and X1 is a bond, alkylene, heteroalkylene, cycloalkylene, or cycloheteroalkylene, each of which is optionally substituted; or R1 and X1 together with the attached nitrogen form an optionally substituted heterocyclyl;
R is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is optionally substituted;
L1 is —C(O)—, —OC(O)—, —NR7C(O)—, —S(O)n—, or —CR7R8A—; where n is 1 or 2; and R7 and R8A are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, hetero alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted, or R7 and R8A together with the carbon atom to which they are attached form an optionally substituted cycloalkyl;
L2 is —C(O)— or —S(O)p—, where p is 1 or 2;
R5A is alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is optionally substituted;
R20 is independently in each instance hydrogen or a pro-drug moiety;
L3 is —C(O)—, —C(O)O—, —C(O)NR4—, —NR20C(O)—, —S(O)q—, —NR20S(O)q—, optionally substituted alkylene, —CH(C(O)NR9AR10A)—, —CH(C(O)OR9A)—, or —CH(S(O)rR9A)—; where q is 1 or 2; r is an integer from 0 to 2; and R9A and R10A are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted, or R9A and R10A together with the attached nitrogen form an optionally substituted heterocyclyl; and
R4A is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted; and R3A is hydrogen, alkyl, alkenyl, heteroalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, each of which is optionally substituted, —NR20R6a, -alkylene-SR11A-alkylene-OR11A, -alkylene-NR11AR12A; where R6a is hydrogen, alkyl, alkenyl, heteroalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, each of which is optionally substituted, -alkylene-SR11A, -alkylene-OR11A, or -alkylene-NR11AR12A; where R11A and R12A are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted; or R11A and R12A together with the attached nitrogen form an optionally substituted heterocyclyl; or R4A and R3A together with L3 and the attached nitrogen form an optionally substituted mono or bicyclic heterocycle;
providing that the compound is not
and
providing that when L3 is C(O), R4A is aryl, or heteroaryl, each of which is optionally substituted, or R4A and R3A together with L3 and the attached nitrogen form an optionally substituted heterocycle.
In another illustrative embodiment, a compound of the following Formula III is described.
and solvates, hydrates and pharmaceutically acceptable salts thereof; wherein:
A is a divalent aromatic group;
R1 is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted; and X1 is a bond, alkylene, heteroalkylene, cycloalkylene, or cycloheteroalkylene, each of which is optionally substituted; or R1 and X1 together with the attached nitrogen form an optionally substituted heterocyclyl;
R is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is optionally substituted;
L4 is —C(O)—, —S(O)n—, or —CR7R8A—; where n is 1 or 2; R7 and R8A are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or R7 and R8A together with the carbon atom to which they are attached form an cycloalkyl, each of which is optionally substituted;
L2 is —C(O)— or —S(O)p—, where p is 1 or 2;
R5A is alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each of which is optionally substituted;
R20 is hydrogen or a pro-drug moiety;
L5 is —C(O)—, —S(O)q—, NR9A, optionally substituted alkylene, —CH(C(O)NR9AR10A)—, —CH(C(O)OR9A)—, or —CH(S(O)rR9A)—; where q is 1 or 2; r is an integer from 0 to 2; and R9A and R10A are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted, or R9A and R10A together with the attached nitrogen form an optionally substituted heterocyclyl;
R4A is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted; R3B is hydrogen, alkyl, alkenyl, heteroalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, each of which is optionally substituted, -alkylene-SR11A, alkylene-OR11A or -alkylene-NR11AR12A, where R11A and R12A are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each of which is optionally substituted, or R11A and R12A together with the attached nitrogen form an optionally substituted heterocyclyl; or R4A and R3B together with L5 and the attached nitrogen form an optionally substituted heterocycle;
with the proviso that the compound is not

In another embodiment, methods for treating AIDS, HIV, and other AIDS-related diseases are described herein, where the method includes the step of administering to a patient in need of relief from the disease a therapeutically effective amount or one or more compounds of Formulae I, II, and/or III.
In another embodiment, methods for treating AIDS, HIV, and other AIDS-related diseases are described herein, where the method includes the step of administering to a patient in need of relief from the disease a therapeutically effective amount of one or more compounds of Formula IV, or a composition containing one or more compounds of Formula IV
or a pharmaceutically acceptable salt, isomer, mixture of isomers, crystalline form, non crystalline form, hydrate, or solvate thereof; wherein
R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
Q1 is a cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each of which is optionally substituted;
X1A is a bond, —N(R17)—, —S(O)q—, or optionally substituted alkylene; and R1A is —S(O)2R14, —C(O)R12, —N(R8)R9, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted, or R1A and X1A together with the attached nitrogen form an optionally substituted heterocyclyl;
X2 is —C(O)—, —S(O)n—, or optionally substituted alkylene;
X3 is —C(O)— or —S(O)p—;
X4 is a bond, —C(O)—, —S(O)q—, —N(R17)—, optionally substituted alkylene, —CH(C(O)R12)—, or —CH(S(O)nR11)—;
X5 is a bond, —N(R17)—, —S(O)q—, or optionally substituted alkylene;
R2 and R3 are each independently selected from the group consisting of hydrogen, —S(O)2R14, —C(O)R12, —N(R8)R9, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted; R4 and R5 are each independently selected from the group consisting of hydrogen, halogen, —OH, —NO2, —N(R8)R9, —S(O)nR11, —C(O)R12, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted; or R3, R4, X4 and the attached nitrogen form an optionally substituted heterocyclyl;
p is independently 1 or 2 in each instance; and n and q are each independently 0, 1, or 2 in each instance;
R20 is hydrogen, or a prodrug forming group;
R8 is in each instance independently selected from the group consisting of hydrogen, —C(O)R13, —S(O)2R14, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R9 is in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R10 is in each instance independently selected from the group consisting of —C(O)R13, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R11 is in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, when n is 0; R11 is in each instance independently selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, when n is 1; and R11 is in each instance independently selected from the group consisting of —N(R15)R16, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, when n is 2;
R12 and R13 are each independently selected from the group consisting of hydrogen, —OR19, —N(R18)R19, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted;
R14 is in each instance independently selected from the group consisting of hydrogen, —N(R18)R19, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted; and
R15, R16, R17, R18, and R19 are in each instance independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted.
In another embodiment, pharmaceutical compositions comprising one or more compounds of Formulae I, II and/or III are described herein.